RESUMO
Endocrine-resistant ER+HER2- breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine-resistant BC remain elusive. Here, analysis of the RNA-sequencing data from ER+HER2- BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine-resistant BC cells, not immune cells. Indeed, compared with endocrine-sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS-STING pathway is attenuated in endocrine-resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS-STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2- BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine-resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine-resistant BC.
Assuntos
Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Proteínas de Membrana , Nucleotidiltransferases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Feminino , Humanos , Camundongos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Retroalimentação Fisiológica , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Ischemic stroke is the most common cerebrovascular disease, and vascular obstruction is an important cause of this disease. As the main method for the management of carotid artery stenosis, carotid endarterectomy (CEA) is an effective and preventive treatment measure in ischemic cerebrovascular disease. This study aims to propose the application of a new enhanced recovery after surgery (ERAS) nutritional support regimen in CEA, which can significantly improve the perioperative nutritional status of patients. A total of 74 patients who underwent CEA were included and randomly divided into two groups: 39 patients received nutritional therapy with the ERAS protocol (ERAS group) and 35 patients received routine perioperative nutritional support (control group). Our results showed that the levels of major clinical and biochemical parameters (albumin, hemoglobin, creatinine, calcium and magnesium levels, etc.) in the ERAS group were significantly higher than those in the control group after surgery (p < 0.05). Additionally, patients in the ERAS group had dramatically shorter postoperative length of stay and reflected higher mean satisfaction at discharge (p < 0.001). Moreover, no statistically significant differences were observed in postoperative complication rates and Mini-mental State Examination scores at discharge. The emergence of this neurosurgical ERAS nutritional support program can effectively intervene in perioperative nutritional status, and notably reduce postoperative hospital stays.